This invention relates to therapeutic organic compounds and uses thereof, particularly the treatment of chemokine and chemokine receptor mediated diseases.
Inflammatory reactions are generally characterized by dramatic movement of leukocytes and fluids from the bloodstream into the inflamed tissues. Chemotactic factors such as C5a, leukotriene B4 (LTB4), and platelet-activating factor (PAF) are thought to mediate the migration of all types of leukocytes in inflammation. However, pathologically, it has been suggested that the types of infiltrating cell populations will vary depending largely upon the stimuli and the interval from the injury (Chemokines in Disease, Biology and Clinical Research; (1999) Edited by Caroline A. Hebxc3xa8rt; Humana Press, Totowa, N.J.).
Many different names have been applied to Interleukin-eight (IL-8), such as neutrophil attractant/activation protein-one (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF) and T-cell lymphocyte chemotactic factor. IL-8 is understood to be a chemoattractant for neutrophils, basophils and a subset of T-cells. It is thought to be produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1xcex1, IL-1xcex2 or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP (Baggiolini, M. et. al., (1989) J. Clin. Invest. 84, 1045; Schroder, J. et. al., (1987) J. Immunol. 139, 3474; ibid, (1990) J. Immunol. 144, 2223; Strieter et. al., (1989) Science 243: 1467; ibid, (1989) Journal of Biological Chemistry 264: 10621; Cassatella et. al., (1992) Journal of Immunology 148: 3216).
Chemokines are chemotactic cytokines that belongs to a large family of chemoattractant molecules involved in the directed migration of immune cells (Schall, T. The Chemokines. In The Chemokine Handbook; Thompson, A., Ed., Academic Press: San Diego, Calif., 1994; pp419-460). The physiological role generally assigned to chemokines in the immune process is to elicit mobilization of immune cells against pathogenic organisms by direct recruitment and activation. Based on their structural similarity, chemokines may be subdivided into four subfamilies, CXC, CC, C and CX3C, depending on the position of their first two cysteine residues.
In addition to IL-8, GRO-xcex1, GRO-xcex2, GRO-xcex3 and NAP-2 also belongs to the chemokine xcex1-family. Like IL-8, these chemokines have also been referred to by different names. For instance, GRO-xcex1, -xcex2, -xcex3 have been referred to as MGSA-xcex1, -xcex2, and -xcex3, respectively (Melanoma Growth Stimulating Activity) (Richmond et. al., (1986) J. Cell Physiology 129, 375; and Chang et. al., (1992) J. Immunol. 148, 451). Current understanding is that all of the chemokines of the xcex1-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor.
IL-8, GRO-xcex1, GRO-xcex2, GRO-xcex3 and NAP-2 have been reported to promote the accumulation and activation of neutrophils, and these chemokines have accordingly been implicated in a wide range of acute and chronic inflammatory disorders, including psoriasis and rheumatoid arthritis (Baggiolinni et. al (1992) FEBS Lett. 307, 97; Miller et. al., (1992) Crit. Rev. Immunol. 12, 17; Oppenheim et. al., (1991) Annu. Rev. Immunol. 9, 617; Seitz et. al., (1991) J. Clin. Invest. 87, 463; Miller et. al., (1992) Am. Rev. Respir. Dis. 146, 427; Donnely et. al., (1993) Lancet 341, 6430).
IL-8 has been found to stimulate a number of functions of human neutrophils, including induction of shape change (Thelen, M. et. al., (1988) FASEB J. 2, 2702-2706), release of lysosomal enzymes (Peveri, P. et. al., (1988) J. Exp. Med. 167, 1547-1559), generation of superoxide (Thelen, M. et. al., (1988) FASEB J. 2, 2702-2706), generation of biolipids (Schroder, J. M. (1989) J. Exp. Med. 170, 847-863), and increased expression of adhesion molecules on neutrophils (Paccaud, J. P. et. al., (1990) Biochem. Biophys. Res. Comm. 166, 187-192). It has chemotactic activity not only for neutrophils but also basophils (White, M. V. et. al. (1989) Immunol. Lett. 22, 151-154) and IL-3- or granulocyte-macrophage colony-stimulated factor (GM-CSF)-primed eosinophils (Warringa, R. A. J. et. al., (1991) Blood 77, 2694-2700). IL-8 also induces chemotaxis against CD4+ and CD8+ human peripheral blood T lymphocytes (Larsen, C. G. et. al., (1989) Science 243, 1464-1466). IL-8 enhances the growth-inhibitory activity of neutrophils to Candida albicans (Djeu, J. Y. et. al (1990) J. Immunol. 144, 2205-2210).
IL-8 is also thought to act on nonleukocytic cells such as melanoma cells and synovial fibroblasts (Unemori, E. N. et. al., (1993) J. Biol. Chem. 268, 1338-1342) in vitro. IL-8 reportedly enhances viral replication, particularly cytomegalovirus, in human fibroblasts in vitro (Murayama, T. et. al., (1994) J. Virol 68, 7582-7585). IL-8 may significantly inhibit the antiviral activities of interferon-xcex1 (Khabar, A. S. A. et. al., (1996) Eur. Cytokine Netw. 7, 554). IL-8 may also increase the adhesion of unstimulated human umbilical cord vein endothelial cells (HUVECs) (Gimbrone, M. A. Jr. et. al., (1989) Science 246, 1601-1603), enhance transendothelial migration (Huber, A. R. et. al., (1991) Science 254, 99-102) and induce angiogenesis in rat cornea (Koch, A. E. et. al., Science 258, 1798-1801).
The production of IL-8 in various human diseases has been extensively studied. Clinically, IL-8 has been identified in skin lesions of psoriasis (Schroder J. M. and Christopher E. (1986) J. Invest. Dermatol. 87, 53-58). IL-8 has also been detected in synoval fluids in patients with rheumatoid arthritis (Brennan, F. et. al., (1990) Eur. J. Immunol. 20, 2141-2144), osteoarthritis (Symon, J. A. et al., (1992) Scand. J. Rheumatol. 21, 92-94; Kaneko, S. et. al., (2000) Cytokines Cell Mol. Ther. 6(2) 71-79), and gout (Terkeltaub, R. et. al., (1991) Arthritis Rheum. 34, 894-903), suggesting a pathological role for IL-8 in the establishment of arthritis. Increased IL-8 levels have also been detected in other biological fluids such as bronchoalveolar lavage fluids (BALF), pleural fluids (Carrxc3xa8, P. et. al., (1991) J. Clin. Invest. 88, 1802-1810), and urine (Broaddus, V. C. et. al., (1992) Am. Rev. Repir. Dis. 146, 825-830). Levels of IL-8 in BALF reportedly increase in patients with adult respiratory distress syndrome (ARDS) (miller, E. J. et. al., (1991) Am. Rev. Repir. Dis. 146, 427-432) and idiopathic pulmonary fibrosis (Carrxc3xa8, P. et. al., (1991) J. Clin. Invest. 88, 1802-1810). Elevated serum and bronchoalveolar lavage fluid levels of IL-8 and granulocyte colony-stimulating factor (G-CSF) have been associated with the acute chest syndrome (ACS) in patients with sickle cell disease (Abboud, M. R. et. al., (2000) Br. J. Haematol. 111 (2) 482-490). Urinary IL-8 level increase in patients with urosepsis (Olszyna, D. P. et. al., (2000) J. Infect. Dis. 182 (6) 1731-1737), urinary tract infection (UTI), and several types of glomerulonephritis such as Ig A nephropathy, acute glomerulonephritis (AGN), purpura nephritis, membranous proliferative glomerulonephritis (MPGN), and lupus nephritis (Wada, T. et. al., (1994) Kidney Int. 46, 455-460). These clinical observations have been taken to imply that detection of IL-8 in biofluids from patients may be an important indicator of the acute inflammatory diseases.
Colonization of the gastric mucosa with Helicobacter pylori is reportedly associated with a dense infiltration of granulocytes into the lamina propria in the active phase of gastritis. In one study, antral biopsies from 27 patients with H. pylori-associated gastritis and 25 from H. pylori-negative individuals were analyzed for epithelial cell-derived neutrophil-activating protein 78 (ENA-78) and IL-8 mRNA by semiquantitative reverse transcription (RT)-PCR (Rieder, G. et. al., (2001) Infect. Immun. 69(1) 81-88). Only viable H. pylori yielded a strong ENA-78 and IL-8 induction, while H. pylori outer membrane proteins or water-soluble proteins had no significant effect. These findings may be taken as indicative of the importance of both IL-8 and ENA-78 in the development and perpetuation of H. pylori associated gastritis.
Two receptors for IL-8 are expressed on neutrophils: CXCR-1 (IL-8RA/R1) and CXCR-2 (IL-8RB/R2), (Baggiolini, M. et. al., (1997) Annual Review of Immunology 15: 675-705). These receptors share 77% amino acid sequence identity, and the respective genes are colocalized on chromosome 2q35 (Holmes, W. E. et. al., (1991) Science 253:1278-1280 and Murphy, P. M. and Tiffany, H. L., (1991) Science 253: 1280-1283). One receptor, CXCR-2, reportedly has high affinity for IL-8 and all other CXC chemokines that attract neutrophils (e.g. the GRO proteins, NAP-2, etc.), while the other, CXCR-1, reportedly has high affinity for IL-8 only (Baggiolini, M. et. al., (1994) Adv. Immunol. 55: 97-179). IL-8 receptors are also found on monocytes, basophils, and eosinophils, but the responses of these cells to IL-8 are much weaker than those of neutrophils (Baggiolini, M. et. al., (1994) Adv. Immunol. 55: 97-179).
IL-8 is thought to exert its biological activities by binding to the CXCR-1 and CXCR-2 receptors. Both receptors bind IL-8 with high affinity but have different affinities for MGSA/Groalpha and NAP-2. It has been shown that the expression of epidermal CXCR-2 is increased in psoriasis, suggesting that activation of keratinocytes (KC) mediated by CXCR-2 contributes to the characteristic epidermal changes observed in psoriasis (Kondo, S. et. al., (2000) J. Cell Physiol. 183(3): 366-370).
The participation of inflammatory cells in atherosclerosis is a process that is thought to involve chemotactic cytokines, which may play a role in cellularentry into the vessel wall. Consistent with this, IL-8 and its receptor CXCR-2 are expressed on macrophages (Mphi) in atherosclerosis in mice (Boisvert, W. A. et. al., (2000) Immunol. Res. 21 (2-3), 129-137).
Xu, L and Fidler, I. J. studied the role of IL-8 in the progressive growth of ovarian cancer cells by isolating high- and low-IL-8-produced from the parental Hey-A8 human ovarian cancer cell lines (Xu, L. and Fidler, I. J. (2000) Oncol. Res. 12 (2) 97-106). These studies have been taken to indicate that IL-8 has a direct and indirect growth-potentiating activity in human ovarian cancer cells.
IL-8 (ELR+) was the first CXC chemokine to be found to induce angiogenesis (Keane, M. P. and Strieter, R. M., The Role of CXC Chemokines in the Regulation of Angiogenesis, Mantovani, A. (ed.): (1999) Chemokines, Chem. Immunol. Basel, Karger 27: 86-101). IL-8 was shown to mediate both in vitro endothelial cell chemotactic and proliferative activity, as well as in vivo angiogenesis in the absence of preceeding inflammation using bioassays of angiogenesis (Strieter, R. M. et. al., (1992) American Journal of Pathology 141: 1279-1284). IL-8 has been found to be significantly elevated in non-small cell lung cancer (NSCLC) (Smith, D. R. et. al., (1994) Journal of Experimental Medicine 179: 1409-1415). In Addition, IL-8 was determined to be a major angiogenic factor contributing to overall tumor-derived angiogenic activity in NSCLC (Arenberg, D. A. et. al., (1995) Journal of Investigation Medicine 43: (suppl 3) 479A) and in human pancreatic adenocarcinoma (Le, X. et. al., (2000) J. Interferon Cytokine Res. 20 (11), 935-946).
In various aspects, the invention provides methods for the use of chemokine-receptor-binding compounds (which may be chemokine receptor ligands such as chemokine receptor agonists or antagonist), and/or salts thereof, in treating chemokine mediated diseases or chemokine receptor mediated diseases, such as IL-8 mediated diseases, or diseases mediated by chemokine receptors CXCR-1, and CXCR-2.
In some embodiments, the invention relates to methods of using a compound of formula (I), or a pharmaceutically acceptable salt thereof, to formulate a medicament for the treatment of a chemokine mediated disease state, or to treat such a disease: 
In the foregoing formulae: xe2x80x9caxe2x80x9d may be 0 or an integer from 1 to 4; xe2x80x9cbxe2x80x9d may be 0 an integer from 1 to 4; xe2x80x9ccxe2x80x9d at each occurance may independently be 0 or an interger from 1 to 3.
In some embodiments, ring A may be aromatic and may be heterocyclic with one or more heteroatoms selected from the group consisting of oxygen and nitrogen. In Formula I xe2x80x9cXxe2x80x9d may for example be a hetroatom selected from the group consisting of oxygen and nitrogen. Ring B may be aromatic or non-aromatic and may be substituted at different positions by the groups consisting of alkyl, alkenyls, alkynyls, amino, amido, thio, thiazolo, imidazolo, or aromatic hydrocarbons.
In alternative embodiments, R1 and R2 at each occurance may independently be selected from substituents having 50 or fewer atoms, wherein the substituent may be selected from the group consisting of: H; substituted or unsubstituted alkyls, such as: C1-10 alkyls, C1-6 alkyls; substituted or unsubstituted cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstituted alkenyls, such as C2-6 alkenyls; substituted or unsubstituted alkynyls, such as C2-6 alkynyls; substituted or unsubstituted aryls; substituted or unsubstituted heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; esters; xe2x80x94CF3; xe2x80x94CN; and combinations thereof.
In alternative embodiments, R3, and R4 at each occurance may independently e selected from substituents having 18 or fewer atoms, wherein the substituent may be selected from the group consisting of: H; substituted or unsubstituted alkyls, such as C1-5 alkyls; substituted or unsubstitued cycloalkyls, such as C3-5 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-5 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; such as benzyl and benzyl esters; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; imidazoles; thiazoles; phosphonates; phosphines; carbonyls; carboxyls; silyls; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; esters; xe2x80x94CF3; xe2x80x94CN; and combinations thereof.
In some embodiments, the chemokine may be selected from the group consisting of: IL-8, and chemokines that bind to a chemokine receptor in a mammal selected from the group consisting of CXCR-1, and CXCR-2.
In various embodiments, the invention provides for the use of compounds of the invention in the treatment of diseases selected from the group consisting of inflammation, chronic and acute:inflammation, psoriasis, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthritis, allograft rejection, chronic transplant rejection, asthma, atherosclerosis, mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, atopic dermatitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute chest syndrome in sickle cell disease, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, septic shock, endotoxic shock, urosepsis, glomerulonephritis, lupus nephritis, thrombosis, graft vs. host reaction, angiogenesis, NSCLC, ovarian cancer, pancreatic cancer, breast carcinoma, colon carcinoma, rectum carcinoma, lung carcinoma, oropharynx carcinoma, hypopharynx carcinoma, esophagus carcinoma, stomach carcinoma, pancreas carcinoma, liver carcinoma, gallbladder carcinoma, bile duct carcinoma, small intestine carcinoma, urinary tract carcinoma, kidney carcinoma, bladder carcinoma, urothelium carcinoma, female genital tract carcinoma, cervix carcinoma, uterus carcinoma, ovarian carcinoma, choriocarcinoma, gestational trophoblastic disease, male genital tract carcinoma, prostate carcinoma, seminal vesicles carcinoma, testes carcinoma, germ cell tumors, endocrine gland carcinoma, thyroid carcinoma, adrenal carcinoma, pituitary gland carcinoma, skin carcinoma, hemangiomas, melanomas, sarcomas, bone and soft tissue sarcoma, Kaposi""s sarcoma, tumors of the brain, tumors of thenerves, tumors of the eyes, tumors of the meninges, astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas, meningiomas, solid tumors arising from hematopoietic malignancies (such as leukemias, chloromas, plasmacytomas and the plaques and tumors of mycosis fungoides and cutaneous T-cell lymphoma/leukemia), and solid tumors arising from lymphomas.